tbuckley/cabot-search huggingface dataset:
P03.05.B PRIMARY GAMMA KNIFE RADIOSURGERY FOR PINEAL REGION TUMORS, A SYSTEMATIC REVIEW AND POOLED ANALYSIS OF AVAILABLE LITERATURE WITH HISTOLOGICAL STRATIFICATION
Authors: F Gagliardi, P De Domenico, E Garbin, M Bailo, S Snider, P Mortini
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Pineal region tumors (PTs) represent extremely rare pathologies, characterized by highly heterogeneous histological patterns. Most of the available evidence for Gamma Knife radiosurgical (GKSR) treatment of PTs arises from multimodal regimens, including GKSR as an adjuvant modality following surgery or as a salvage treatment at recurrence. We aimed to gather the existing evidence on the topic and analyze single-patient level data to address the efficacy and safety of primary GKSR when only a biopsy was attempted or biochemical or neuroimaging diagnosis was available. MATERIAL AND METHODS This is a systematic review of literature (Pubmed, Embase, Cochrane, Science Direct) and pooled analysis of single-patient-level data. A total of 1054 original works were retrieved. After excluding duplicates and irrelevant works, we included 13 papers in our final analysis comprising 64 patients. Additional 12 patients were included from the authors’ original series. RESULTS A total of 76 patients reached the final analysis. Presumptive diagnoses included intrinsic pineal low-grade (46%), glial low-grade (LGG, 5%), pineoblastoma (4%), germ cell tumors (GCTs, 4%), pineal tumors of intermediate differentiation (3%), other pineal tumors (3%), glial high-grade (HGG, 2%) and meningioma (1%). In 32% of cases, the diagnosis was unclear. Only 57% of cases received histological confirmation. The mean age at treatment was 38.7y and the mean lesional volume was 4.2 ± 4 cc. All patients received GKSR with a mean marginal dose (50% isodose) of 14.7 ± 2.1 Gy. At a median 36mo follow-up, local control was achieved in 84% of cases. Ten patients showed progression within a mean time of 24.2mo. Progression was more common in HGG and GCTs (p=0.03) compared to intrinsic pineal tumors. Overall mortality was 13.2%. The median OS was not reached for all included lesions, except high-grade gliomas (8mo). The 3y-OS was 100% for LGG, 90% for the intrinsic pineal, 60% for GCTs, 50% for HHG, and 82% for undetermined tumors. The 3y-PFS was 100% for LGG, 90% for the intrinsic pineal, 32% for GCTs, and 0% for HHG. Median PFS was 5mo for HHG and 34mo for GCTs. The radionecrosis rate was 6%, and cystic degeneration was observed in 2%. Ataxia as presenting symptom strongly predicted mortality (OR 104, p=0.02), while GCTs and HHG histology well predicted PD (OR: 13, p=0.04). CONCLUSION These results support the efficacy and safety of primary GKSR treatment of pineal region tumors. Further studies are needed to validate these results, which highlight the importance of the initial presumptive diagnosis for choosing the best therapeutic strategy.
P02.23.A MDM2/X ALTERATIONS IN A MULTICOHORT RETROSPECTIVE ANALYSIS: A POTENTIAL TARGET OF TREATMENT IN PATIENTS WITH PRIMARY BRAIN TUMORS
Authors: D Gomez Puerto, K Vega Cano, G Molina Lores, C Salva de Torres, D Lopez Valbuena, O Mirallas, M Gonzalez, M Vieito
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Primary brain tumors (pBTs) are a heterogeneous group of neoplasms with limited therapeutic alternatives. Disruption of the TP53 tumor suppressor pathway occurs in most high-grade gliomas. While TP53 loss-of-function mutations are poorly targetable, in 14% of patients this disruption is due to a Mouse double minute 2 homolog (MDM2) amplification. We aim to describe the characteristics of patients with MDM2 amplification and analyze its clinical and molecular factors using a cohort of patients with NGS data. MATERIAL AND METHODS Patients currently enrolled in the institutionally approved, retrospective multicenter study ESCAT-pBTs, which includes patients with pBT profiled used NGS methods (Foundation Medicine®, local NGS, Caris®, Oncomine®, copy number alterations (CNA), and fusion panels) were analyzed to determine the presence of MDM2 alterations (MDM2alt) and clinical factors including WHO 2021 diagnosis, sex, age, ECOG and other molecular findings. RESULTS A total of 493 pts with NGS and CNA were collected between Feb 2018 and January 2023 at 5 hospitals in Spain. The median age was 50.3 (range, 3.3-83.8), 14.2% had ECOG ≥2, 39.1% were women, 26.9% were 40 or younger, 21.5% had IDH1mut and 24.3% were methylated. The diagnosis of GBM (WHO 2021) was present in 68.8% of the patients and 33.8% had mutations or CNV in TP53. The overall prevalence of MDM2alt was 8.5%(42 pts), 92.9% gene amplifications, and 7,1% mutations. No differences were found in gender proportion between MDM2alt and no MDM2alt (Female: 37.1% vs 39.4% p:0.64) and no major variance in the percentage of ECOG ≥2 (16.6% vs 17.6% p:0.77). Prevalence in patients with GBM was: 11.8% vs 1.3% in patients with other pBTs. Concurrent mutations in MDM2alt patients were: CDK-4 copy number gain in 76,2%; a similar proportion of mutations in PI3KCA/PTEN was observed compared with the non-MDM2alt population in the pts with GBM (38,3% vs 50%, p:0.15). No significant variation was found in EGFR amplifications (42,9% vs 32% p:0.10) and EGFR mutations GBM MDM2 and no MDM2alt respectively (19% vs 18,7% p: 0.84). The median TMB was 5.22 (range from 2.24 to 13 mutations/megabase) in pts with MDM2alt and 4.76 (range from 1.26 to 53.7 mutations/megabase). 97,6% of the MDM2alt population was TP53 wild type. CONCLUSION MDM2alt is a common genomic event in patients with molecularly defined GBM and has a low prevalence in other pBT. The presence of MDM2alt is associated in our series with other genomic events such as PTEN loss, low TMB, and a high degree of CDK4 amplification. No statistically significant differences were found between the GBM MDM2alt and no MDM2alt subgroup in terms of molecular alterations and clinical aspects studied. These findings should inform the further clinical development of treatment strategies for MDM2alt pts.
P13.07.B IMMUNE AND CELL PROLIFERATION PATHWAYS CONTRIBUTE TO THE SEX DIFFERENCES IN A-TO-I RNA EDITING-BASED SUBTYPING OF GLIOBLASTOMA
Authors: S Chen, S Wong
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND A-to-I RNA editing has been recently identified as a sex-specific prognostic factor for glioblastoma (GBM). However, the underlying molecular mechanisms of sexual dimorphism are still understudied. We aimed to identify genes displaying sexual dimorphism in patient survival and investigate their involvement in the pathogenesis of GBM. METHODS We performed differential expression analyses on bulk RNA-Seq data between GBM patients with distinct survival rates, controlling for sex and the sex-survival interaction. Two principal components that captured the effects of both survival and the sex-survival interaction were constructed to rank genes for gene set enrichment analysis (GSEA). We also analyzed single-cell RNA-Seq data to evaluate the interactions of sexually dimorphic genes between different cell types. RESULTS A negative correlation was found between survival and the sex-survival interaction, indicating a substantial proportion of DEGs with sexually dimorphic prognostic value. GSEA revealed that immune-related pathways exhibited higher expression in males with a favorable prognosis, while females with a poor prognosis showed elevated expression levels in these pathways. Conversely, cell proliferation and stemness pathways were more highly expressed in males with a poor prognosis, whereas females with a favorable prognosis displayed higher expression levels in these pathways. Additionally, we found 22 DEG-associated cell-cell interactions, many of which were between macrophage/microglia and tumors. CONCLUSION Our findings suggest that sexual dimorphism of RNA editing may be attributed to cell proliferation and immune-related pathways. Moreover, our results provide valuable insights into the underlying mechanisms of cellular communication during the pathogenesis of GBM.
P08.06.B OPTUNE TREATMENT FOR PATIENTS WITH GLIOBLASTOMA: A MIXED METHOD STUDY OF PATIENTS´, NEXT OF KIN´S´, PHYSICIANS´ AND COMPANY STAFFS´ EXPERIENCES
Authors: N Letter, L Kastbom, E Wahlberg, J Norrgård, E Degsell, M Karlsson, A Malmström
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Since the pivotal trial, showing a near 5-month survival advantage with the addition of Optune to standard treatment for glioblastoma (GBM), Optune has been introduced into clinical practice in many countries. In Sweden, the device is prescribed by physicians, while the service of equipment and control of its use occur in the patients’ home by staff from the private company providing the device, this potentially creating a conflict of interest. Also, the daily use of the device necessitates the help of a next of kin. These are unique arrangements for Swedish healthcare, leading to the need of a complex and possibly challenging collaboration, and also raising potential ethical dilemmas.This study investigates Optune treatment for patients with GBM, regarding experiences of those involved in the treatment, namely: patients, next of kin, physicians and staff from the private company providing the device. MATERIAL AND METHODS The aim is to include 20 or more participants in each group (patients and next of kin, respectively). They are individually interviewed. The interviews are transcribed and analyzed using quantitative content analysis. Electronic questionnaires were sent during 2021-2022 to all physicians prescribing Optune at Departments of Oncology or Neurology in Sweden. The questionnaires included quantitative as well as open ended questions. Staff working for the company and visiting the patients and next of kin have also received electronic questionnaires focusing on experiences from their work. RESULTS Challenges were identified by the physicians, but they had varying opinions on the magnitude of the ethical problems. To date, 10 patients and 9 next of kin have been interviewed. Possible categories already identified are: “Information from the healthcare” and “Patient - company staff collaboration”. The questionnaires to the staff have been answered. The results of the interviews with patients and next of kin, as well as the results of the questionnaires to staff, will be presented. CONCLUSION The INTRODUCTION of Optune as a treatment of patients with GBM constitutes a new concept and a need for new solutions for tackling medical, practical and ethical issues. SUPPORT The Medical Research Council of Southeast Sweden (FORSS), and an ALF grant from Region Östergötland.
P21.05.B CAPTURING EVOLVING DEFINITIONS OF 12 SELECT RARE CNS TUMORS: A TIMELY REPORT FROM CBTRUS AND NCI-CONNECT
Authors: M Price, C Neff, C Kruchko, K Waite, G Cioffi, J Barnholtz-Sloan, B Cordeiro, P J Cimino, M R Gilbert, T S Armstrong, Q Ostrom
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Histopathology-specific incidence, prevalence, and survival are essential population-based cancer statistics that describe cancer burden. The National Cancer Institute’s Comprehensive Oncology Network Evaluating Rare CNS Tumors (NCI-CONNECT) aims to improve understanding of tumor biology and patient outcomes for 12 selected rare brain and other central nervous system (CNS) tumor types to improve approaches to care and treatment. These types included atypical teratoid/rhabdoid tumor, brainstem and midline gliomas, choroid plexus tumors, ependymomas, high grade meningiomas, gliomatosis cerebri, medulloblastoma, oligodendrogliomas, pineal region tumors, pleomorphic xanthoastrocytomas, CNS embryonal tumors, NEC/NOS and primary CNS sarcoma. The analysis aimed to estimate the incidence (new cases per year), prevalence (currently living cases), and survival rates for these selected rare brain and other CNS tumor types. MATERIAL AND METHODS The Central Brain Tumor Registry of the United States (CBTRUS) data, which contains data from the Centers for Disease Control and Preventions National Program of Cancer Registries (NPCR) and National Cancer Institute’s Surveillance, Epidemiology and End Results (SEER) data, from 2008-2019 were used to calculate average annual age-adjusted incidence rates (AAAIR) per 100,000 population overall and by sex, race/ethnicity, and age. Incidence time trends were calculated for diagnosis years 2004-2019. NPCR survival data from 2001-2018 were used to calculate relative survival (RS) estimates. Estimated prevalence counts as of December 31, 2019 were estimated using incidence from CBTRUS and overall survival rates from SEER. RESULTS Overall AAAIR for all 12 subtypes combined was 1.51 per 100,000 population, with the highest subtype-specific incidence in ependymomas (AAAIR=0.41/100,000). Overall, most subtypes were more common in males and people who are non-Hispanic White. Incidence of all subtypes varied by age. Ependymomas were most prevalent with 19,339 cases; followed by oligodendrogliomas with 15,070 cases. Time trends in incidence varied by subtype, with significant decreases in incidence of gliomatosis cerebri, CNS embryonal tumor, and primary CNS sarcoma. RS for all subtypes combined at 1, 5, and 10 years was 86.6%, 71.9%, and 65.3%, respectively. Ependymomas had the highest RS (1-year=96.1%, 5-years=90.6%, 10-years=86.6%) and primary CNS sarcomas had the lowest RS (1-year=48.2%, 5-years=7.7%, 10-years=5.2%). CONCLUSION Incidence, prevalence, and survival patterns for these 12 selected rare cancer subtypes varied significantly by type. Population based data are critical to guiding effective design of and accrual expectations for clinical trials in rare cancers.
PL01.5.A NEOADJUVANT CAMRELIZUMAB AND APATINIB IN PATIENTS WITH RECURRENT HIGH-GRADE GLIOMAS:PRIMARY REPORT OF AN OPEN LABEL PHASE II STUDY
Authors: Z Chen, C Guo, Q Yang, W Hu, X Cao, Y Liao, J Zhang, X Jiang, D Li, Y Chen
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND Recurrent high-grade gliomas (HGG) is a challenge with a poor prognosis and limited treatment options. A study has reported that neoadjuvant immunotherapy upregulates PD-L1 expression and CD8+T cell infiltration, which is expected to improve the survival of HGG. Our study (NCT04588987) aimed to assess the efficacy and safety of perioperative camrelizumab (anti-PD-1 antibody) and apatinib (antiangiogenic agent) in patients with recurrent HGG. METHODS Patients with recurrent HGG received 14 days of neoadjuvant treatment with camrelizumab (intravenous injection 200 mg on day 1) and apatinib (oral 250 mg per day on days 1-7), followed by surgery for recurrent tumor. Sequential therapy began 2 weeks after surgery with the biweekly camrelizumab (200mg) and 4 weeks after surgery with the daily apatinib (250mg) until investigator-assessed progressive disease or unable to tolerate toxicity. The primary endpoint was overall survival (OS). RESULTS Between Oct 9, 2020 and Feb 14, 2023, 18 patients have been enrolled (14 for recurrent glioblastomas, 3 for anaplastic astrocytoma and 1 for anaplastic oligodendroglioma). At the data cut-off (Mar 31, 2023), 16 patients discontinued study treatment (12 cases of disease progression, 1 case of liver function injury, 1 case of COVID-19 infection, 1 case refused treatment and 1 case died before progression). The median treatment time for camrelizumab and apatinib were 4.8 (95% CI: 3.8-5.9) months and 5.2 (95% CI: 3.9-6.4) months, respectively. The median OS was 12.9 months (95% CI: 9.3-16.4) with a median follow-up time of 17.5 (95%CI:9.0-26.1) months. The median PFS was 4.8 months (95% CI: 4.4-5.2). Nine (50%) patients occurred grade 3 treatment-related adverse events (TRAEs). Decreased lymphocyte count (22.2%, 4/18), hypertension (16.7%,3/18) and Increased aspartate aminotransferase (11.1%,2/18) were the most common grade 3 TRAEs, and there were no grade 4 or 5 TRAEs. CONCLUSION This combination therapy in recurrent HGG demonstrated encouraging efficacy, and TRAEs are manageable.Keywords: Apatinib, Camrelizumab, Neoadjuvant therapy, Recurrent high-grade gliomas.
PL02.2.A RAPID, COMPREHENSIVE REPORTING OF MOLECULAR DIAGNOSTICS WITH RAPID-CNS2: A PROSPECTIVE VALIDATION COHORT
Authors: A Patel, F Hinz, H Dogan, A Payne, K Göbel, D Schrimpf, M Ritter, E Krause, L Pfeifer, M Krech, C Blume, D Stichel, V Goidts, L Schweizer, A Unterberg, W Wick, S Pfister, M Sill, M Loose, A von Deimling, D T W Jones, M Schlesner, F Sahm
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND The WHO classification of CNS tumours 2021 recommends reporting a wide range of molecular alterations for WHO-compatible diagnoses. Conventional molecular diagnostic workflows warrant considerable investment and long turnaround times limited by batching. Nanopore sequencing enables long read sequencing, real-time targeting and simultaneous base modification detection with compact devices. Rapid-CNS2- a rapid, comprehensive adaptive sampling based sequencing pipeline with a turnaround time of 5 days for CNS tumours was previously described. This study presents an optimised Rapid-CNS2 pipeline and prospective validation cohort that successfully reports hard-to-detect variants. MATERIAL AND METHODS We performed targeted adaptive sampling-based sequencing on 156 samples comprising a mix of archival and current diagnostic cases from the Department of Neuropathology, University Hospital Heidelberg. We tested variable conditions including minimum DNA input, target size, flowcell reuse and sequencing times. An analysis pipeline for detection of single nucleotide variants (SNV), indels, copy number alterations (CNA), fusions, complex structural variants (SV), target gene methylation and methylation classification incorporating multi-GPU optimization was deployed. Results were compared to NGS panel sequencing and EPIC array analyses. RESULTS Integrated diagnoses for all cases were in accordance with those issued using molecular alterations reported by conventional analyses. Rapid-CNS2 showed improved resolution over NGS panel sequencing for CNAs. Complete concordance was achieved for MGMT promoter methylation status and methylation classification. High accuracy was obtained for detection of SNV/Indels. Long reads spanning the breakpoint identified clinically relevant fusions. Subclonal SVs including EGFR vIII missed by NGS panel sequencing were detected with high confidence. The optimized workflow shortened the turnaround time to 30 hours from sample receipt to report and minimum input DNA required was reduced to 500ng. Due to the versatility of adaptive sampling, the analyses can readily be limited to a smaller set of targets or methylation and CNAs only, further reducing the turnaround time. CONCLUSION We present a thorough validation and prospective clinical application of Rapid-CNS2 with cases spanning a range of brain tumours and metastases. The improved custom neurooncology adaptive sampling-based sequencing pipeline enables simultaneous copy-number, mutational, structural variant and methylation analysis with flexible target selection, no additional library preparation, competitive costs and next-day reporting of RESULTS
P14.02.B LONGITUDINAL COMPARATIVE ANALYSIS OF BLOOD NEUROFILAMENTS AS BIOMARKERS OF CHEMOTHERAPY-INDUCED PERIPHERAL NEUROTOXICITY
Authors: R Velasco, C Marco, G Ferrer, E Domingo-Domènech, A Stradella, C Santos, B Laquente, A Argyriou, J Bruna
Journal: Neuro-Oncology (2023)

Abstract BACKGROUND The identification of a biomarker of chemotherapy-induced peripheral neurotoxicity (CIPN) remains an unmet need. Increasing evidence supports that light-chain Neurofilament (NfL) could be useful to quantify the extend of peripheral nerve damage due to chemotherapy. The aim of the study is to ascertain differences in plasma NfL (pNfL) among agents to evaluate the clinical usefulness of pNfL. MATERIAL AND METHODS Prospective longitudinal comparative study including patients treated with paclitaxel (N=24) for breast cancer, brentuximab vedotin (BV) (n=20) for lymphoma and oxaliplatin (n=16) for gastrointestinal cancer. All patients were assessed using the Total Neuropathy Score-clinical, Common Toxicity Criteria for Adverse Events before (T1), at finishing (T2) and at next follow-up (T3). Serial pNfL were collected at the same timepoints and quantified using the SIMOA technique. The changes in pNfL were compared between group of agents (platinum (oxaliplatin) or microtubule disruptors (MT) (BV or paclitaxel) and correlated with clinical data, depending on the degree of CIPN. Clinically relevant (CR) was defined as &amp;gt; grade 2-CIPN. RESULTS 60 patients are included, mostly women (66,7%) with median age of 52 [22-88] years. pNfL at T1 was 16,51 ± 1,65 pg/mL, and correlated with age (r= 0.284, p &amp;lt; 0.036). pNfL increased at T2 (141,39 ± 18,89 pg/mL) and decreased at last follow-up (T3) (28,08 ± 2,52 pg/mL) in the whole series, at a median of 3 (1-5) months after finishing chemotherapy. Patients with CR-CIPN had higher pNfL at T2 (209,90 ± 40,09 vs 103.02 ± 96.74 pg/mL, p=0.005). One third of patients receiving MT disruptors (31,6%) or platinum agents (35,7%) developed CR-CIPN. Higher pNfL level at T2 were identified in patients receiving anti MT agents than oxaliplatin (160, 27 ± 22,75 vs 70,04 ± 11,24 pg/mL), p&amp;lt;0,001). Among the group of MT, pNfL at T2 were higher in those receiving paclitaxel compared to BV (233,90 ± 31.84 vs 62,09 ± 9.60 pg/mL, p&amp;lt;0.001), despite no differences in rate of CR-CIPN (26,6% BV and 34.7% Paclitaxel, p=0.7). At T3, no differences in pNfL were identified between BV (33,53 ± 4,67 pg/mL) and paclitaxel (29,20 ± 4,24 pg/mL) treated patients. A significant correlation between pNfL and TNSc was identified (r = 0.663, p &amp;lt; 0.001). CONCLUSION Variable change of pNfL according to the type of agent and mechanism of neurotoxicity can be observed regardless of the comparable degree of clinical CIPN severity. Further studies to better dissect cut-off values for each agent are needed before implementing pNfL as CIPN biomarker.